Infection with the hepatitis B virus (HBV) can lead to chronic hepatitis and hepatocellular carcinoma. Current therapies for chronic HBV infection are only moderately effective, and are limited by severe side effects and viral resistance. Thus, there remains a need for new therapies for this serious disease. The host T cell response to HBV is vigorous and multi-specific in acutely infected people who clear the virus, but it is weak and narrowly focused in those who become chronically infected. Therapeutic vaccination to induce an immune response sufficient to control the virus is a possible new approach for the treatment of chronic hepatitis B. Unfortunately;the current HBV vaccine is not effective for therapeutic vaccination. Although it produces a strong neutralizing antibody response that prevents infection, it does not induce the potent CD8 T cell response needed to eliminate the virus after infection. The current vaccine is also not optimal for widespread prophylactic vaccination in endemic underdeveloped regions of the world, as it does not induce protection in all individuals, the protective antibody response decreases over time, and multiple doses are required for long-lasting immunity. Recombinant vesicular stomatitis virus (VSV) vaccine vectors induce strong protective CD8 T cell and antibody responses to a variety of pathogens, and are also showing promise as therapeutic vaccines. We will test the hypothesis that recombinant VSV expressing the HBV structural proteins will make effective vaccines for prophylactic and therapeutic immunization against HBV. We will generate recombinant VSV vaccine vectors that express HBV proteins, characterize the immune response to VSV/HBV in vaccinated animals, and determine if VSV/HBV vaccine vectors induce an effective immune response in mouse models of chronic HBV. An improved prophylactic vaccine that provides long-term immunity in a single dose or an effective therapeutic vaccine would have the potential to prevent millions of cases of HBV-associated hepatocellular carcinoma. Public Health Relevance: Chronic hepatitis B virus (HBV) infection leads to millions of deaths each year worldwide from liver cirrhosis and hepatocellular carcinoma. Current therapies for HBV infection are only moderately effective, and are often accompanied by severe side effects and viral resistance. An improved prophylactic vaccine and/or an effective therapeutic vaccine would have the potential to prevent millions of cases of HBV-associated liver cancer.